UC Irvine Molecular Biologists Discover Key Protein Interaction That Stabilizes Cholesterol Levels in Cells

Irvine, Calif., June 7, 2000 -- UC Irvine researchers who study the link between nutrition and molecular activity in the body have discovered how a major regulatory protein stabilizes cholesterol levels in cells, a finding that may provide further clues on how genetics influence heart disease, stroke and diabetes.

Timothy F. Osborne and Mary K. Bennett of UCI's Department of Molecular Biology and Biochemistry isolated a key regulating protein as it bound with other proteins to initiate the gene activity that stabilizes blood levels of cholesterol. To do this, the scientists used an observational method--called the chromatin immunoprecipitation technique (CHIPS)--new to their research, which for the first time allowed observation of this interaction within living cells.

Their findings appear in the June 6, 2000 issue of Proceedings of the National Academy of Sciences. Understanding how proteins react to cholesterol levels in cells gives researchers greater information on how to adjust this activity to balance these levels in people who have irregular amounts of cholesterol in their blood.

Although cholesterol is important for maintaining cell structure and rigidity, high levels of certain types of cholesterol are significant contributing factors to heart disease and stroke, two of the leading causes of death among American adults.

"If we can understand more about how these regulatory proteins work, we can find ways to make their interaction more efficient and independent of the cholesterol levels within the cells," Osborne said. "Therapeutically, we may be able to develop ways to have cells remove excess cholesterol from the blood to keep it from accumulating there, which can lead to the buildup of arterial plaque and to potential heart attacks and strokes."

By using the CHIPS observational technique, Osborne and Bennett studied a group of proteins, called sterol regulatory element binding proteins, that regulate cholesterol and fatty acid levels in cells.

In addition to other regulatory activity, these binding proteins react to changing cholesterol levels by activating genes that either remove excess cholesterol from the blood or create more cholesterol when cellular levels are low.

In the study, the researchers observed that when cholesterol levels are low, these proteins recruit a co-regulating protein called Sp1 to a specific binding site on cells' DNA. The interaction of these two proteins activates the low-density lipoprotein (LDL) receptor, which then balances cholesterol levels in the blood. Sp1 is found in virtually all cells and is involved with many cellular processes including DNA repair and synthesis.

Although the researchers believed that the protein may be involved in cholesterol regulation, the finding is the first proof that Sp1 is directly linked with this activity in intact cells.

The discovery, Osborne said, is an important step in understanding how regulatory binding proteins trigger genetic activity that metabolizes cholesterol in cells.

"Once we identify these key regulatory proteins and how they work in normal cells, we will be able to predict how they might function improperly in people who have difficulty regulating their cholesterol levels," Osborne said. "We can use this information to design ways to make the regulatory system work more efficiently."

Osborne plans to continue using the CHIPS method to identify other genes that participate with these binding proteins. The knowledge gained from this research, Osborne said, may lead to the development of screening methods for key metabolizing genes that are defective in people who develop high cholesterol.

"If you can identify the genetics early enough, you can anticipate potential high cholesterol problems and suggest an alternative lifestyle to keep patients healthy," Osborne said. "In addition, since these binding proteins stimulate the conversion of blood sugars into fats, this research may also give insights into the genetic activity that leads to diabetes, which is principally a defect in the metabolism of sugars and fats."

The study was supported in part by the National Institutes of Health, the American Diabetes Association and the American Heart Association.

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